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10 reviewsSmall cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized Received: 20 December 2022by rapid proliferation, early metastatic spread, frequent early relapse and a high Accepted: 18 July 2025mortality rate1–3. Recent evidence has suggested that innervation has an important role in the development and progression of several types of cancer4,5. Cancer-toPublished online: xx xx xxxxneuron synapses have been reported in gliomas6,7, but whether peripheral tumours Open accesscan form such structures is unknown. Here we show that SCLC cells can form Check for updatesfunctional synapses and receive synaptic transmission. Using in vivo insertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identifed neuronal, synaptic and glutamatergic signalling gene sets in mouse and human SCLC. Further experiments revealed the ability of SCLC cells to form synaptic structures with neurons in vitro and in vivo. Electrophysiology and optogenetic experiments confrmed that cancer cells can receive NMDA receptor- and GABAA receptor-mediated synaptic inputs. Fitting with a potential oncogenic role of neuron–SCLC interactions, we showed that SCLC cells derive a proliferation advantage when co-cultured with vagal sensory or cortical neurons. Moreover, inhibition of glutamate signalling had therapeutic efcacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells seem to hijack synaptic signalling to promote tumour growth, thereby exposing a new route for therapeutic intervention.